Efficacy in diet-induced obese mice of the hepatotropic, peripheral cannabinoid 1 receptor inverse agonist TM38837.

BACKGROUND AND PURPOSE: The cannabinoid CB1 receptor has a well-established role in appetite regulation. Drugs antagonizing central CB1 receptors, most notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals but were discontinued due to psychiatric side effects. However, metabolic benefits were only partially attributable to weight loss, implying a role for peripheral receptors, and peripherally restricted CB1 receptor antagonists have since been of interest. Herein, we describe the evaluation of the peripherally restricted potent CB1 receptor inverse agonists TM38837 and TM39875, with acidic functionality, which were administered daily to diet-induced obese (DIO) mice for 5 weeks at doses for which CNS-mediated effects were minimal. EXPERIMENTAL APPROACH: Compounds were tested in dose-response in acute studies to compare efficacy (gastric transport) and extent of CNS exposure (hypothermia and satiety sequence) to demonstrate peripheral restriction and select doses for the subsequent chronic DIO study. KEY RESULTS: TM38837 but not TM39875 produced considerable (26%) weight loss, linked to a sustained reduction in food intake, together with improvements in plasma markers of inflammation and glucose homeostasis. Pharmacokinetic analysis indicated high plasma and low brain levels for both compounds with high liver levels for TM38837 (but not TM39875) due to hepatic uptake. CONCLUSION AND IMPLICATIONS: Weight loss and metabolic benefits of TM38837 are likely not CNS-mediated but could be linked to enhanced liver exposure, which implicates intracellular CB1 receptors in hepatocytes as a possible driver of obesity and co-morbidities.

Multiple Dose Pharmacokinetics of Tapentadol Oral Solution for the Treatment of Moderate to Severe Acute Pain in Children Aged 2 to <7 Years.

Background: This prospective, open-label trial was conducted to fulfil a post-approval commitment made to the competent authorities to extend the indication of the strong opioid analgesic tapentadol hydrochloride oral solution (OS) to the pediatric population. Patients and Methods: The trial assessed the pharmacokinetic (PK) profile of tapentadol, tapentadol-O-glucuronide and tapentadol-O-sulfate after administration of multiple doses of tapentadol OS (1.25 mg tapentadol/kg bodyweight every 4 h for up to 72 h) in children aged 2 to <7 years after a painful event that produces acute pain requiring treatment with a strong analgesic. The obtained PK data were integrated into a previously developed population PK (popPK) model based on single-dose data and then a model-based PK evaluation was performed. The primary trial endpoint was the area under the concentration-time curve at steady state for the dosing interval (AUCτ,ss) for tapentadol. Results: Ten children received tapentadol OS; all completed the trial. Multiple administrations of the trial medication resulted in tapentadol serum concentrations within the concentration range predicted by the previously developed popPK model. The estimated model-based AUCτ,ss values for tapentadol ranged from 142 to 321 h•ng/mL. They were within the predicted exposure range with no higher than expected accumulation for the employed dosing regimen and also within the targeted steady state exposure range observed in adults receiving multiple doses of immediate release tapentadol 50 to 100 mg. The treatment regimen was safe and well tolerated. Conclusion: The findings confirm the linear and predictable PK profile of tapentadol hydrochloride. The good agreement between the observed data and the model predictions shows the value of modelling and simulations in the planning and analysis of pediatric clinical trials and the ability to utilize the established PK models to predict multiple dose exposure.

Tapentadol prolonged release in patients with chronic low back pain: real-world data from the German Pain eRegistry.

Aim: Comparison of tapentadol prolonged release (PR) with other oral WHO-III PR opioid analgesics (morphine, oxycodone ± naloxone, hydromorphone) in routine medical care of chronic low back pain. Patients & methods: Noninterventional, retrospective 12-week study using anonymized clinical practice data from the German Pain eRegistry. Six effectiveness, tolerability, and safety criteria were aggregated in a primary composite end point (treatment responder). Propensity scoring matched 2331 datasets per treatment cohort. Results: All six single criteria showed significantly better outcomes for tapentadol PR (all parameters p < 0.001). There were significantly more treatment responders under tapentadol PR (65.7 vs 14.2%; p < 0.001). Conclusion: Tapentadol PR showed significantly better effectiveness and tolerability in severe chronic low back pain unsuccessfully treated with WHO-I/II analgesics compared with the other oral WHO-III PR opioids investigated.

Lay abstract Chronic low back pain is a common condition often resulting in impaired functioning in daily life and reduced quality of life and well-being of the patient. In case treatment with less potent pain medications is unsuccessful, opioid treatment might be required. Our study compared the effectiveness and tolerability of the prolonged release formulation of the atypical opioid tapentadol with other strong opioids commonly used for chronic pain treatment in Germany (morphine, hydromorphone, oxycodone ± naloxone). Anonymized patient data from German clinical practices collected in a pain registry were used (2331 comparable patients per treatment group). Patients receiving 12 weeks of tapentadol treatment experienced significantly greater pain relief, greater improvements in daily living activities, sleep, and quality of life compared with those receiving the other strong opioids investigated. Neuropathic pain components (pain features resembling nerve pain, often described as shooting, burning or stabbing pain) were reduced to a greater extent in the tapentadol treatment group. Tapentadol was also significantly better tolerated. This study showed that tapentadol is effective and well tolerated in chronic low back pain treatment in routine medical practice in patients still in considerable pain despite treatment with less potent pain medications.

Outcomes of the Pediatric Development Plan of Tapentadol.

The opioid analgesic tapentadol was the first pain medication to be developed for the treatment of pain in children under a formal process established by the regulatory authorities. This article summarizes the outcomes of the pediatric development program for tapentadol across the entire age range from birth (including neonates) to adolescents <18 years of age. In addition, the challenges experienced when designing and conducting the pediatric tapentadol clinical trials as well as the interactions with the regulatory authorities are discussed. As a first outcome, the oral solution of tapentadol was authorized in the EU in 2018 as a new treatment option in the hospital setting for moderate to severe acute pain in children from 2 to <18 years of age.

Tapentadol Prolonged Release for Severe Chronic Osteoarthritis Pain in the Elderly-A Subgroup Analysis of Routine Clinical Practice Data.

Background: Tapentadol prolonged release (PR) has been shown effective and generally well tolerated in a broad range of chronic pain conditions. This subgroup analysis investigated its benefits for elderly patients with severe chronic osteoarthritis (OA) pain in routine clinical practice. Patients and Methods. Data of all patients with chronic OA pain were extracted from the database of a prospective, 3-month noninterventional tapentadol PR trial. The data of elderly OA patients (>65 years of age; n = 752) were compared with the data of younger OA patients (≤65 years; n = 282). Results: Almost all patients (elderly 98.7% and younger patients 99.3%) had received long-term analgesic medication prior to the start of tapentadol PR treatment but presented with severe pain accompanied by considerable impairments in sleep quality and quality of life measures. Tapentadol PR provided effective pain relief in both patient groups, with slightly better outcomes in younger patients. However, the mean baseline pain intensity of 7.1 (SD 1.5) was reduced by 3.8 points (p ≤ 0.001), and sleep and quality of life measures had also markedly improved in the elderly: quality of sleep by 3 points, quality of life by 3.4 points, social activities by 3 points, and independence by 2.7 points (p ≤ 0.001 for all measures; 11-point scale). At the end of observation, 68% of the elderly had clinically relevant pain reductions of at least 50% (vs baseline), and 87.9% attained either their intended pain reduction target and/or an additional individual treatment target (both predefined during baseline examination). Only 8.4% of the elderly experienced adverse drug reactions, most frequently nausea (2.7% of patients) and dizziness (1.5%). Conclusion: Tapentadol PR provided effective and well-tolerated treatment of severe chronic OA pain for elderly patients in routine clinical practice. The favorable tolerability profile in particular suggests tapentadol PR as a treatment option before classical strong opioids are considered.

Tapentadol prolonged release for severe chronic osteoarthritis pain in the elderly: improvements in daily functioning and quality of life.

Background: Chronic osteoarthritis (OA) pain leads to severe impairments in physical functioning and quality of life. Patients & methods: Data of patients with severe chronic knee and/or hip OA pain were extracted from the database of a prospective, noninterventional trial to assess the benefits of tapentadol prolonged release (PR) in elderly patients (>65 years of age; n = 1162) compared with younger patients (≤65 years of age; n = 498). Results: Tapentadol PR treatment (up to 3 months) significantly reduced pain intensity and pain-related restrictions on daily functioning and significantly improved physical and mental quality of life in both patient groups. The incidence of adverse drug reactions was low. Conclusion: Tapentadol PR is a useful strong analgesic to improve pain intensity, physical functioning and quality of life in elderly OA patients.

The Cannabinoid CB1 Antagonist TM38837 With Limited Penetrance to the Brain Shows Reduced Fear-Promoting Effects in Mice.

Rimonabant was the first selective CB1 antagonist/inverse agonist introduced into clinical practice to treat obesity and metabolic-related disorders. It was withdrawn from market due to the notably increased rates of psychiatric side effects. We have evaluated TM38837, a novel, largely peripherally restricted CB1 antagonist, in terms of fear-promoting consequences of systemic vs. intracerebral injections. Different groups of male C57BL/6 N mice underwent auditory fear conditioning, followed by re-exposure to the tone. Mice were treated per os (p.o.) with TM38837 (10, 30, or 100 mg/kg), rimonabant (10 mg/kg; a brain penetrating CB1 antagonist/inverse agonist which served as a positive control), or vehicle, 2 h prior the tone presentation. Only the high dose of TM38837 (100 mg/kg) induced a significant increase in freezing behavior, similar to that induced by rimonabant (10 mg/kg) (p < 0.001). If injected into the brain both TM38837 (10 or 30 µg/mouse) and rimonabant (1 or 10 µg/mouse) caused a sustained fear response to the tone, which was more pronounced after rimonabant treatment. Taken together, TM38837 was at least one order of magnitude less effective in promoting fear responses than rimonabant. Given the equipotency of the two CB1 antagonists with regard to weight loss and metabolic syndrome-like symptoms in rodent obesity models, our results point to a critical dose range in which TM3887 might be beneficial for indications such as obesity and metabolic disorders with limited risk of fear-promoting effects.

Does 'Strong Analgesic' Equal 'Strong Opioid'? Tapentadol and the Concept of 'µ-Load'.

INTRODUCTION: The distinct properties of the centrally-acting analgesic tapentadol derive from the combined contributions of an opioid component and a nonopioid component. However, the opioid component's relative contribution to analgesic and adverse effects has not previously been elucidated. Tapentadol's analgesic effect derives from the combined contribution of an opioid mechanism and a nonopioid mechanism, the extent of which can vary for different pains. Likewise, the interaction can vary for various adverse effects. Hence, the contribution of each mechanism to adverse effects can be different from the contribution to analgesia. We here estimate the percent contribution of each component of the mechanism of action to analgesia and to adverse effects. AREAS COVERED: Several approaches to in vitro and in vivo data to estimate the contribution of tapentadol's opioid component to analgesia and to the two important opioid adverse effects, respiratory depression and constipation. The results are then compared with clinical data. EXPERT OPINION: Traditional opioids, such as morphine, oxycodone, and others, produce their analgesic effects primarily through a single mechanism-the activation of µ-opioid receptors (MOR). Therefore, the contribution of the opioid component to adverse effects is 100%. In contrast, the newer strong analgesic tapentadol produces its analgesic effect via two separate and complementary analgesic mechanisms, only one of which is µ-opioid. We applied standard drug-receptor theory and novel techniques to in vitro and in vivo data to estimate by several different ways the µ-load of tapentadol (the % contribution of the opioid component to the adverse effect magnitude relative to a pure/classical µ-opioid at equianalgesia) in respiratory depression and constipation, and we compared the results to clinical evidence. The estimate is remarkably consistent over the various approaches and indicates that the µ-load of tapentadol is ≤ 40% (relative to pure MOR agonists, which have, by definition, a µ-load of 100%). FUNDING: Grünenthal GmbH.

Efficacy and safety of tapentadol prolonged release formulation in the treatment of elderly patients with moderate-to-severe chronic osteoarthritis knee pain: a pooled analysis of two double-blind, randomized, placebo-, and active-controlled trials.

OBJECTIVE: To compare efficacy and safety of tapentadol prolonged release (PR) vs oxycodone controlled release (CR) in younger patients (<65 years of age) and in elderly patients (≥65 and ≥75 years of age) in the treatment of moderate-to-severe chronic osteoarthritis (OA) knee pain. METHODS: Data from two double-blind, randomized, placebo-, and oxycodone CR-controlled phase 3 trials were pooled and stratified by age. Primary efficacy end-points were change from baseline in average pain intensity at week 12 (US end-point) and over the entire maintenance period (non-US end-point). RESULTS: A total of 1357 patients <65 years, 653 patients ≥65 years, and 176 patients ≥75 years of age were assessed. The comparison between tapentadol PR and oxycodone CR showed numerically better pain relief under tapentadol PR for both primary end-points in all three age groups. More favorable improvements were also observed for patient global impression of change, the Short Form-36 physical component score, and EuroQoL-5Dimensions health status index. In the elderly, incidences of dizziness and somnolence were comparable between active treatments, but incidences of nausea, vomiting, and constipation were considerably lower under tapentadol PR. Treatment completion rates were lowest under oxycodone CR; > 50% of elderly oxycodone CR patients named side-effects as the main reason for discontinuation. CONCLUSIONS: Tapentadol PR was effective in the treatment of moderate-to-severe chronic OA pain in elderly and younger patients. Compared to oxycodone CR, the overall and the gastrointestinal tolerability profile in particular were better in all tapentadol PR groups, regardless of age.

Review of Post-Marketing Safety Data on Tapentadol, a Centrally Acting Analgesic.

INTRODUCTION: Tapentadol is a centrally acting analgesic that has been available for the management of acute and chronic pain in routine clinical practice since 2009. METHODS: This is the first integrated descriptive analysis of post-marketing safety data following the use of tapentadol in a broad range of pain conditions relating to the topics overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsion. The data analyzed pertain to spontaneous reports from healthcare and non-healthcare professionals and were put in the context of safety information known from interventional and non-interventional trials. RESULTS: The first years of routine clinical practice experience with tapentadol have confirmed the tolerability profile that emerged from the clinical trials. Moreover, the reporting of expected side effects such as respiratory depression and convulsion was low and no major risks were identified. The evaluation of available post-marketing data did not confirm the theoretical risk of serotonin syndrome nor did it reveal unexpected side effects with administration of higher than recommended doses. CONCLUSION: More than 8 years after its first introduction, the favorable overall safety profile of tapentadol in the treatment of various pain conditions is maintained in the general population. FUNDING: Grünenthal GmbH.

Efficacy and safety of tapentadol prolonged release for moderate-to-severe chronic osteoarthritis knee pain: a pooled analysis of two double-blind, randomized, placebo- and oxycodone controlled release-controlled studies.

OBJECTIVE: To compare efficacy and safety of tapentadol prolonged-release (PR) and oxycodone-controlled release (CR) in moderate-to-severe chronic osteoarthritis knee pain. METHODS: Data from two double-blind, randomized, placebo- and oxycodone CR-controlled phase 3 studies with a 3-week titration period and 12-week controlled dose adjustment maintenance period were pooled. Primary efficacy end-points were change from baseline in average pain intensity at week 12 (US end-point) and over the entire maintenance period (non-US end-point). RESULTS: A total of 2,010 patients were assessed. For both primary end-points, tapentadol PR was significantly more effective than oxycodone CR (LS mean difference of -0.41 [95% CI = -0.65, -0.16; p = 0.001] at week 12 and -0.35 [95% CI = -0.58, -0.12; p = 0.003] over 12 weeks of maintenance [last observation carried forward]). Significantly better outcomes than for oxycodone CR were also observed for patient global impression of change, both Short Form-36 component scores, and EuroQoL-5Dimensions health status index (all p < 0.001). Relative risk for vomiting, constipation, nausea, somnolence, and pruritus was lower for tapentadol PR than for oxycodone CR. A higher proportion of oxycodone CR patients discontinued treatment (64% vs 42.2% for tapentadol PR); time to treatment discontinuation due to an adverse event was significantly shorter for oxycodone CR (p < 0.001). CONCLUSIONS: The analyses suggest that tapentadol PR provided superior pain relief and a more improved overall health status than oxycodone CR in a large patient population with moderate-to-severe chronic osteoarthritis pain. Compared to oxycodone CR, tapentadol PR showed a more favorable tolerability profile with better gastrointestinal tolerability.

Low brain CB1 receptor occupancy by a second generation CB1 receptor antagonist TM38837 in comparison with rimonabant in nonhuman primates: a PET study.

Both central and peripheral cannabinoid receptor type 1 (CB1R) have been considered to be among the key targets for obesity treatment. First generation CB1R antagonists/inverse agonists such as rimonabant and taranabant exhibited severe CNS side effects such as anxiety and depression, which are considered to be related to the compounds' ability to access central CB1R. Recently, several compounds have been developed as second generation antagonists with a profile of restriction to peripheral CB1R. We evaluated the distribution of TM38837, a second generation CB1R antagonist, using brain and whole body PET in three cynomolgus monkeys, and established the relationship between CB1R occupancy and dose/plasma concentration of TM38837 in comparison with rimonabant. A brain PET study was performed using [(11) C]MePPEP, a PET radioligand for CB1R, to evaluate the brain CB1R occupancy of TM38837 at various plasma concentrations in comparison with rimonabant at known efficacious plasma concentrations. A whole body PET study was performed to investigate the change of peripheral distribution of [(11) C]MePPEP by TM38837 administration, which indirectly estimated the effects to the peripheral CB1R by TM38837. CB1R occupancy by both TM38837 and rimonabant increased in a dose/plasma concentration-dependent manner. However, in vivo affinity by plasma level was more than 100 times lower for TM38837. Peripherally, [(11) C]MePPEP accumulation decreased in gall bladder and brown adipose tissue by TM38837 administration. TM38837 showed rather lower CB1R occupancy than rimonabant at the expected therapeutic plasma level, which is expected to reduce CNS side effects in clinical situations. Further clinical development of TM38837 is warranted.

Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects.

AIM: Cannabinoid receptor type 1 (CB1 ) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist TM38837 was studied in humans. METHODS: This was a double-blind, randomized, placebo-controlled, crossover study. On occasions 1-4, 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic (PD) effects were assessed frequently. Pharmacokinetics (PK) and PD were quantified using population PK-PD modelling. RESULTS: The TM38837 plasma concentration profile was relatively flat compared with rimonabant. TM38837 showed an estimated terminal half-life of 771 h. THC induced effects on VAS feeling high, body sway and heart rate were partly antagonized by rimonabant 60 mg [-26.70% [90% confidence interval (CI) -40.9, -12.6%]; -7.10%, (90%CI -18.1, 5.3%); -7.30%, (90% CI -11.5%, -3.0%) respectively] and TM38837 500 mg [-22.10% (90% CI -34.9, -9.4%); -12.20% (90% CI -21.6%, -1.7%); -8.90% (90% CI -12.8%, -5.1%) respectively]. TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects. CONCLUSIONS: Rimonabant showed larger effects than TM38837, but the heart rate effects were similar. TM38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.

Integrative analyses for omics data: a Bayesian mixture model to assess the concordance of ChIP-chip and ChIP-seq measurements.

The analysis of different variations in genomics, transcriptomics, epigenomics, and proteomics has increased considerably in recent years. This is especially due to the success of microarray and, more recently, sequencing technology. Apart from understanding mechanisms of disease pathogenesis on a molecular basis, for example in cancer research, the challenge of analyzing such different data types in an integrated way has become increasingly important also for the validation of new sequencing technologies with maximum resolution. For this purpose, a methodological framework for their comparison with microarray techniques in the context of smallest sample sizes, which result from the high costs of experiments, is proposed in this contribution. Based on an adaptation of the externally centered correlation coefficient ( Schäfer et al. 2009 ), it is demonstrated how a Bayesian mixture model can be applied to compare and classify measurements of histone acetylation that stem from chromatin immunoprecipitation combined with either microarray (ChIP-chip) or sequencing techniques (ChIP-seq) for the identification of DNA fragments. Here, the murine hematopoietic cell line 32D, which was transduced with the oncogene BCR-ABL, the hallmark of chronic myeloid leukemia, was characterized. Cells were compared to mock-transduced cells as control. Activation or inhibition of other genes by histone modifications induced by the oncogene is considered critical in such a context for the understanding of the disease.

Beta-arrestin2 as a competitor for GRK2 interaction with the GLP-1 receptor upon receptor activation.

The signaling of seven transmembrane receptors/G-protein- coupled receptors (GPCRs) is regulated by a number of receptor interacting proteins, including ßarrestins (ßarrs) and GPCR kinases (GRKs). In the present report, we have analyzed the interaction pattern between the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), ßarr2, and GRK2 using bioluminescence resonance energy transfer assays. We found that ßarr2 interacts with the GLP-1R in a biphasic manner with a phosphorylation-independent and a phosphorylation-dependent component. In competition experiments, we observed ßarr2 competing with GRK2 for interaction with GLP-1R. We propose a model were ßarr2 competes with GRK2 for interaction with the activated and GRK phosphorylated GLP-1R, suggesting a new role of ßarr2 in regulating the orchestration of GRK2 functionality.

Long-acting lipidated analogue of human pancreatic polypeptide is slowly released into circulation.

The main disadvantages of peptide pharmaceuticals are their rapid degradation and excretion, their low hydrophilicity, and low shelf lifes. These bottlenecks can be circumvented by acylation with fatty acids (lipidation) or polyethylene glycol (PEGylation). Here, we describe the modification of a human pancreatic polypeptide analogue specific for the human (h)Y(2) and hY(4) receptor with PEGs of different size and palmitic acid. Receptor specificity was demonstrated by competitive binding studies. Modifications had only a small influence on binding affinities and no influence on secondary structure. Both modifications improved pharmacokinetic properties of the hPP analogue in vivo and in vitro, however, lipidation showed a greater resistance to degradation and excretion than PEGylation. Furthermore, the lipidated peptide is taken up and degraded solely by the liver but not the kidneys. Lipidation resulted in prolonged action of the hPP analogue in respect of reducing food intake in mice after subcutaneous administration. Therefore, the lipidated hPP analogue could constitute a potential new therapeutic agent against obesity.

Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease.

The FIP1L1-PDGFRA fusion is seen in a fraction of cases with a presumptive diagnosis of hypereosinophilic syndrome (HES). However, because most HES patients lack FIP1L1-PDGFRA, we studied whether they harbor activating mutations of the PDGFRA gene. Sequencing of 87 FIP1L1-PDGFRA-negative HES patients revealed several novel PDGFRA point mutations (R481G, L507P, I562M, H570R, H650Q, N659S, L705P, R748G, and Y849S). When cloned into 32D cells, N659S and Y849S and-on selection for high expressors-also H650Q and R748G mutants induced growth factor-independent proliferation, clonogenic growth, and constitutive phosphorylation of PDGFRA and Stat5. Imatinib antagonized Stat5 phosphorylation. Mutations involving positions 659 and 849 had been shown previously to possess transforming potential in gastrointestinal stromal tumors. Because H650Q and R748G mutants possessed only weak transforming activity, we injected 32D cells harboring these mutants or FIP1L1-PDGFRA into mice and found that they induced a leukemia-like disease. Oral imatinib treatment significantly decreased leukemic growth in vivo and prolonged survival. In conclusion, our data provide evidence that imatinib-sensitive PDGFRA point mutations play an important role in the pathogenesis of HES and we propose that more research should be performed to further define the frequency and treatment response of PDGFRA mutations in FIP1L1-PDGFRA-negative HES patients.